Alcohol-induced protein hyperacetylation: mechanisms and consequences

Abstract

Although the clinical manifestations of alcoholic liver disease are well-described, little is known about the molecular basis of liver injury. Recent studies have indicated that ethanol exposure induces global protein hyperacetylation. This reversible, post-translational modification on the epsilon-amino groups of lysine residues has been shown to modulate multiple, diverse cellular processes ranging from transcriptional activation to microtubule stability. Thus, alcohol-induced protein hyperacetylation likely leads to major physiological consequences that contribute to alcohol-induced hepatotoxicity. Lysine acetylation is controlled by the activities of two opposing enzymes, histone acetyltransferases and histone deacetylases. Currently, efforts are aimed at determining which enzymes are responsible for the increased acetylation of specific substrates. However, the greater challenge will be to determine the physiological ramifications of protein hyperacetylation and how they might contribute to the progression of liver disease. In this review, we will first list and discuss the proteins known to be hyperacetylated in the presence of ethanol. We will then describe what is known about the mechanisms leading to increased protein acetylation and how hyperacetylation may perturb hepatic function.

Figure 1

Alcohol-induced defects in protein trafficking can be explained by increased microtubule acetylation and stability. Cargo internalized from the basolateral plasma membrane is delivered to the early endosome (EE) and sorted into at least four different pathways. They are recycled directly back to the plasma membrane (e.g. ASGP-R), delivered to the recycling endosome (RE) before recycling back to the plasma membrane (e.g. Tf-R), delivered to lysosomes (lys) (e.g. LY) or to the apical plasma membrane via the sub-apical compartment (SAC) (e.g. APN, pIgA-R and 5’NT). Albumin secretion is also indicated. In ethanol (EtOH) or TSA treated cells, albumin secretion and the internalization of APN, pIgA-R, Tf-R and ASGP-R is impaired whereas the fluid-phase delivery of LY to lysosomes or the raft/caveolae-mediated internalization of 5’NT and CTxB are not changed. In the lower hepatocyte, the various deacetylases and acetyltransferases that may play a role in the acetylation of nonnuclear proteins are indicated.